APPLICANT'S ABSTRACT: The broad goal of our research is to delineate the mechanisms involved in the neurotrophic actions of opioids. The particular focus of this proposal involves identifying elements in the receptor-dependent signalling system mediating opioid inhibition of DNA synthesis in rat brain cell cultures. There are four specific aims: AIM 1) determine whether the neurotrophic action of opioids is dependent on modulation of the synthesis, activity or turnover of protein kinase c; AIM 2) determine whether phospholipase D (PLD) has a role in the mechanism of opioid action; AIM 3) determine whether the neurotrophic action of opioids is dependent on modulation of the synthesis, activity or turnover of mitogen- activated protein (MAP) kinase; AIM 4) establish the nature of the transducer involved in the pertussis toxin- insensitive, mu receptor-mediated action of opioids. A variety of biochemical, immunological, cell biological and molecular biological techniques will be used taking advantage of fetal rat brain cell aggregate, rat C6BU-1 glioma and opioid receptor-transfected CHO cell culture systems, all of which are responsive to opioids. Since maternal drug abuse and its treatment places hundreds of thousands of offspring at risk each year in the United States alone and infants exposed to opiates in utero are afflicted with a range of problems including developmental delays, the answers sought in these studies both have fundamental significance, and bear on an important public health problem.